Angioimmunoblastic T-cell lymphoma (AITL), as a major subtype of peripheral T-cell lymphoma (PTCL), poses significant challenges for clinicians due to its complex pathological features, variable clinical presentation, and poor prognosis. In recent years, with advances in medical research, novel diagnostic techniques and treatment methods for nTFHL have emerged, leading to new breakthroughs in diagnosis and therapy. However, patient outcomes remain bleak, underscoring the urgent need for further basic and clinical research to guide clinical practice and improve prognosis. Recently, Dr. Jianyong Li from Jiangsu Province Hospital provided a detailed overview of the latest research progress in nodal T-follicular helper cell lymphoma (nTFHL). Hematology Frontier has compiled these insights for our readers.

Key Points Summary

• nTFHL (AITL) is a unique subtype of PTCL, characterized histopathologically by clonal T-cell infiltration and prominent neoangiogenesis, originating from TFH cells.
• Comprehensive diagnosis and MRD detection using clinical assessment, IHC, flow cytometry, and ctDNA (ddPCR, NGS) are crucial.
• Molecular diagnosis and prognostic stratification of AITL based on gene expression analysis; certain molecular features may become targets for personalized therapy.
• AITL shows limited response to frontline CHOP, and patients with access should consider frontline ASCT; combination regimens with new drugs offer hope for the future, and HDACi combinations have shown benefits in TFH phenotype lymphomas, though single-agent therapies for R/R AITL remain limited, warranting further exploration of combinations.
• Basic research progress in understanding the pathogenesis of nTFHL may reveal new therapeutic targets.

Overview of nTFHL (AITL)

AITL is one of the common types of PTCL, accounting for 79%. In the 2022 WHO classification (WHO-HAEM5), AITL was renamed as nodal T-follicular helper cell lymphoma – angioimmunoblastic type (nTFHL-AI). The follicular type (nTFHL-F) and not otherwise specified type (nTFHL-NOS) account for 14% and 7%, respectively.

Misdiagnosis or missed diagnosis of nTFHL often occurs due to the lack of specific markers and the complexity of cell composition. For example, pathological diagnosis requires at least two TFH markers, such as PD1, ICOS, CXCL13, CD10, and BCL6. The microenvironment’s cellular components include T cells, B cells, plasma cells, eosinophils, and follicular dendritic cells, among others.

Epigenetic mutations play a key role in the pathogenesis of AITL. Hematopoietic stem/progenitor cells undergo epigenetic mutations in TET2/DNMT3A, representing the first hit in tumorigenesis. These cells, carrying methylation-related mutations, later acquire RHOA and IDH2 mutations, constituting the second hit. These mutations together drive AITL tumor cell development through their effects on cell epigenetic modifications and signaling pathways.

The progression of AITL is primarily related to the microenvironment. Research shows that AITL originates from TFH cells and is closely associated with germinal center B cells and tumor dendritic cells in the tumor microenvironment. When TFH function is disrupted, it leads to disordered germinal centers, eventually progressing to AITL. It’s worth noting that TFH cells are not the primary drivers of AITL’s aggressive progression; the microenvironment, comprising 90% of the tumor mass, plays a critical role, containing a rich presence of non-malignant bystander cells and proliferating high endothelial venules.

TFH cells release cytokines and chemokines that attract and enrich various immune cells, including CD4 and CD8 T cells, B cells, plasma cells, eosinophils, and follicular dendritic cells. Signaling between these cells is crucial for AITL development. TFH cells promote B-cell enrichment through cytokines like IL-21 and IL-4 and establish connections with germinal center B cells via surface antigens like CXCR5, PD-1, and ICOS. Angiogenesis also plays an essential role in AITL progression, with mast cells releasing VEGF to promote vascular development and support tumor growth. Overall, TFH cells and other cells in the microenvironment form a complex network that influences disease progression and treatment strategies.

AITL typically affects middle-aged and elderly patients, with a median onset age between 62 and 67 years. Most AITL patients are diagnosed at an advanced stage, with 81% to 98% of patients at stages III or IV according to the Ann Arbor classification. Common clinical manifestations of AITL include “B symptoms” such as fever, night sweats, and weight loss, present in 60% to 77% of patients; 51% to 65% of patients may experience anemia. AITL may also be accompanied by splenomegaly, hepatomegaly, rash (20%-50%), ascites, and hypergammaglobulinemia. Additionally, approximately 70% of AITL patients have bone marrow involvement. Imaging studies often reveal widespread lymphadenopathy, though large mass lesions are uncommon. The prognosis for AITL is generally poor, with a 5-year overall survival (OS) rate of about 32%-41%.

Compared to B-cell lymphomas, PTCL’s treatment outcomes and survival rates remain suboptimal, with a typically poor prognosis and a high rate of early relapse. The median overall survival (mOS) is less than 2 years, and the 5-year survival rate is below 30%. Although CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) remains a widely used regimen, the survival rate for AITL patients has not significantly improved over the past two decades. Even among patients receiving autologous stem cell transplantation, the 5-year progression-free survival (PFS) is only 24%, and the OS rate is 33%.

Advances in nTFHL (AITL) Diagnosis

Morphological diagnosis often confuses AITL with PTCL-NOS. Studies show that 37% of cases morphologically diagnosed as PTCL-NOS are molecularly classified as other subtypes. Moreover, lymphomas with TFH characteristics have similar molecular features, such as mutations in TET2, DNMT3A, IDH2 (R172), and RHOA (G17V).

Although traditionally challenging to diagnose, new diagnostic technologies have changed this landscape. Peripheral blood flow cytometry can detect nTFHL tumor cells in the blood before lymph node biopsy, with AITL clones detected in 58.8% of AITL patients. Droplet digital PCR (ddPCR) can detect RHOA G17V and IDH2 R172 mutations with a sensitivity of up to one in a thousand. ddPCR results are highly consistent with those from next-generation sequencing (NGS), but ddPCR is more cost-effective and faster. These new technologies provide powerful tools for the differential diagnosis and monitoring of nTFHL, helping to improve diagnostic accuracy and treatment specificity.

ctDNA testing for RHOA G17V can predict AITL outcomes: higher RHOA G17V VAF correlates with poorer response to frontline treatment, PFS, and OS. Monitoring the dynamic changes of RHOA G17V can detect refractory or progressing disease before imaging, with a significant decrease in RHOA G17V in responding patients. Additionally, baseline RHOA G17V correlates well with EBV DNA copy number, with consistent trends during treatment.

Advances in nTFHL (AITL) Treatment

Currently, the frontline treatment for PTCL is CHOP+X, with the emergence of new drugs expanding treatment options.

In 2022, the 5-year follow-up data from the ECHELON-2 study showed that compared with CHOP, frontline treatment with the CD30-targeting antibody-drug conjugate brentuximab vedotin (BV) + CHP improved PFS and OS, with the most significant PFS benefit observed in the ALK+ systemic anaplastic large cell lymphoma (sALCL) subtype, followed by ALK- sALCL, while AITL and PTCL-NOS showed no or minimal benefit.

Histone deacetylase inhibitor romidepsin combined with CHOP for nTFHL treatment also showed no benefit, with an mPFS of 8.7 months, lower than the CHOP group’s 9 months.

Chidamide + prednisone + VP16 + thalidomide (CPET) in initial treatment of AILT achieved an ORR of 90.2% and CRR of 54.9% among 51 patients completing eight cycles, with an overall mPFS of 27.7 months.

Azacitidine + CHOP as frontline therapy for untreated PTCL patients achieved an overall CRR of 75%, with the PTCL-TFH group’s CRR reaching 88.2%.

In dual epigenetic therapy, combining HDAC inhibitors (HDACi) with hypomethylating agents (HMA) showed significant efficacy in treating TFH phenotype T-cell lymphomas. One study reported an ORR and CRR of 61% and 48%, respectively, for azacitidine + romidepsin in PTCL patients, with higher response rates and deeper remissions over time in TFH and treatment-naive patients, especially those with TET2 mutations.

R/R PTCL patients have poorer prognosis, with a 2nd PFS of only 3.7 months and OS of just 6.5 months after chemotherapy. New drugs and combination therapies can improve response rates and survival in R/R PTCL to some extent.

The ORR of HDACi + HMA combination therapy can reach 73%, with a CRR of 55%.

PI3K inhibitor duvelisib + romidepsin for R/R PTCL achieved an ORR of 58% and a CRR of 42%, with the AITL/TFH group achieving an ORR of 68% and a CRR of 58%.

Romidepsin + GemOxDex for R/R PTCL achieved an ORR of 58% and a CRR of 47%, with the AITL group achieving an ORR of 100% (6/6).

Studies show that single-agent epigenetic therapies have moderate activity in R/R PTCL but lack sufficient depth of response. A single-arm Phase I study explored the safety and efficacy of dual epigenetic therapy (azacitidine + chidamide ± GemOx) for R/R PTCL, achieving an ORR of 73.7% and a CRR of 47.4% in the AITL group, superior to chemotherapy alone. AITL patients receiving dual epigenetic therapy combined with GemOx achieved the best response rates (ORR 91.7%, CRR 66.7%) and survival (mPFS 17.2 months, mOS 38.8 months).

Pralatrexate and linperlisib for PTCL achieved ORRs of 40.7% and 48%, respectively, while JAK1 inhibitor golixertinib achieved a preliminary CRR of 56.3% in AITL. EZH2 inhibitors and mitoxantrone liposomes have also shown some efficacy.

Basic Research in nTFHL (AITL)

A key focus of AITL basic research is exploring the remodeling characteristics of the tumor microenvironment and the key molecules and mechanisms of refractory disease. Significant differences exist between the tumor microenvironment of newly diagnosed and refractory AITL. B-cell and myeloid subpopulations play important roles in AITL progression, with B-cells in refractory AITL showing gene expression similarities to DLBCL, indicating malignant potential. The proportion of EBV-positive B-cells is significantly higher in the refractory group than in the newly diagnosed group. The YY1 gene is highly expressed in TFH cells of refractory patients, promoting AITL cell proliferation and resistance. Refractory AITL has reduced CD8+ T-cells, increased Treg proportions, and higher levels of T-cell exhaustion, presenting an overall immunosuppressive state. Recent studies have identified follicular B-cells, endothelial cells, and myofibroblasts as key cell types in the AITL tumor microenvironment, potentially driving malignant progression.

Single-cell level analyses are expected to accurately decode the gene and protein spatial atlas of nTFHL, helping to analyze tumor heterogeneity, the spatial characteristics of malignant T-cells and the microenvironment, interactions between subpopulations, mutation patterns, and spatial distribution during tumor progression, as well as the role of EBV infection and B-cell malignancy in disease progression.

In addition, research is ongoing on T-cell subpopulation expression characteristics, TFH identification, STING-mediated granulocyte/endothelial cell infiltration in the tumor microenvironment, and AITL tumor cells’ expression of histamine receptor type 2 (HRH2).

Expert Profile

Dr.Jianyong Li

• Professor, PhD Supervisor, Postdoctoral Supervisor
• Director of Lymphoma Center, Jiangsu Province Hospital
• Class A Distinguished Professor
• Standing Committee Member of the Hematology Branch, Chinese Medical Association
• Leader of the Lymphocyte Disease Group
• Former Chair of the Hematologic Oncology Committee, Chinese Anti-Cancer Association
• Vice Chair of the Lymphoma Quality Control Expert Committee, National Cancer Quality Control Center
• Leader of the Chinese Chronic Lymphocytic Leukemia Working Group
• Vice Chair of the Lymphoma Expert Committee, CSCO
• Vice Chair of the Lymphoma Group, Oncology Branch, Chinese Medical Association
• President of the Hematology Physician Branch, Jiangsu Medical Doctor Association
• Chair of the Hematology Branch, Jiangsu Medical Association
• Chair of the Hematology Branch, Jiangsu Geriatrics Society
• Honorary Chair of the Hematology Branch, Nanjing Medical Association
• Vice President of the China Hematology Specialty Alliance
• Vice Chair of the Hematology Institutions Branch, China Hospital Association
• Vice Chair of the Hematopoietic Stem Cell Transplantation and Cellular Therapy Professional Committee, China Medical Education Association